 |
PDBsum entry 2gt7
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Crystal structures reveal an induced-Fit binding of a substrate-Like aza-Peptide epoxide to sars coronavirus main peptidase.
|
|
|
Authors
|
|
T.W.Lee,
M.M.Cherney,
J.Liu,
K.E.James,
J.C.Powers,
L.D.Eltis,
M.N.James.
|
|
|
Ref.
|
|
J Mol Biol, 2007,
366,
916-932.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
The SARS coronavirus main peptidase (SARS-CoV M(pro)) plays an essential role in
the life-cycle of the virus and is a primary target for the development of
anti-SARS agents. Here, we report the crystal structure of M(pro) at a
resolution of 1.82 Angstroms, in space group P2(1) at pH 6.0. In contrast to the
previously reported structure of M(pro) in the same space group at the same pH,
the active sites and the S1 specificity pockets of both protomers in the
structure of M(pro) reported here are in the catalytically competent
conformation, suggesting their conformational flexibility. We report two crystal
structures of M(pro) having an additional Ala at the N terminus of each protomer
(M(+A(-1))(pro)), both at a resolution of 2.00 Angstroms, in space group
P4(3)2(1)2: one unbound and one bound by a substrate-like aza-peptide epoxide
(APE). In the unbound form, the active sites and the S1 specificity pockets of
both protomers of M(+A(-1))(pro) are observed in a collapsed (catalytically
incompetent) conformation; whereas they are in an open (catalytically competent)
conformation in the APE-bound form. The observed conformational flexibility of
the active sites and the S1 specificity pockets suggests that these parts of
M(pro) exist in dynamic equilibrium. The structural data further suggest that
the binding of APE to M(pro) follows an induced-fit model. The substrate likely
also binds in an induced-fit manner in a process that may help drive the
catalytic cycle.
|
|
|
|
|
|
|
|
Figure 1.
Figure 1. Inhibition of SARS-CoV M^pro by the aza-peptide
epoxides (APEs) synthesized for our study,
Cbz-Leu-Phe-AGln-EP-CooEt. The epoxide carbon atoms are numbered
and their stereochemistry is omitted for simplicity. The
proposed mechanism for the irreversible inhibition of clan CD
cysteine peptidases by APEs is indicated by arrows. In the
inhibition of M^pro, route I was adopted. Cbz, the
benzyloxycarbonyl group; AGln, aza-glutamine; EP, epoxide;
COOEt, ethyl ester.
|
|
Figure 8.
Figure 8. Aromatic interactions observed between Phe140 and
His163 in the crystal structures of SARS-CoV M^pro (wild type
and variants). The broken lines indicate the alignment of the
partial positive charges (δ+) of the hydrogen atoms on the
phenyl ring of Phe140 with the partial negative charges (δ−)
in the central part of the imidazole ring of His163.
|
|
|
|
|
|
The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2007,
366,
916-932)
copyright 2007.
|
|
|
|
|
|
|
